Abstract Worldwide, stimulants such as methamphetamine rank second only to cannabis in number of users, and in North America, the prevalence of amphetamine abuse is double the global rate. Methamphetamine (meth) is being found to play an increasingly important role in AIDS, as well. Evidence suggests that meth and HIV infection have additive effects on neurocognitive impairment and CNS damage. Meth is a sympathomimetic causing release of norepinephrine from peripheral nerves, and we have shown that norepinephrine promotes HIV and SIV replication. Meth's effects on the CNS, then, could be an indirect consequence of its ability to release norepinephrine from sympathetic varicosities in secondary lymphoid tissue, leading to greater viral replication and higher viral loads, and greater numbers of circulating, infected cells (primarily monocytes) that can enter the CNS. Meth's effects in the CNS could also result from effects on the blood-brain barrier (BBB). Independent lines of evidence suggest that meth, stress (a precipitating factor for much drug use, including methamphetamine), and HIV/SIV can all contribute to weakening the blood-brain barrier. We propose that these three factors could have additive effects, resulting in increased transport across the BBB of blood borne factors such as infected monocytes and inflammatory cytokines, leading to a greater likelihood of CNS infection and damage, and neuropsychological impairment. Finally, given our demonstrated effects of stress on viral replication in lymph nodes, and the additional effects we anticipate seeing due to the sympathomimetic properties of methamphetamine, we propose that beta adrenergic receptor blockade or administration of recombinant interferon-beta will abrogate the effects of methamphetamine and stress in the lymph node. Our specific aims are 1) to examine the role played by methamphetamine and stress in alterations in innervation patterns, Type I interferon gene expression, and SIV replication in lymph nodes, and disease-related indicators in blood;2) to examine the role played by methamphetamine and stress in altering permeability of the blood-brain barrier in SIV infected monkeys;3) to examine whether beta adrenergic receptor blockade or administration of recombinant interferon-beta will abrogate the effects of methamphetamine in lymph nodes and at the BBB. Relevance This research will provide new information on the mechanisms by which methamphetamine, a major drug of abuse in the United States, leads to increased structural and functional changes in the brains of HIV-infected people. We propose that the negative effects of methamphetamine in lymph nodes and at the blood-brain barrier can be prevented through use of commonly available medications. If our hypotheses are confirmed in our animal model, these medications could be used as adjunct treatments to the more usual anti-HIV therapies.